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Ref Type Journal Article
PMID (31371345)
Authors Krook MA, Bonneville R, Chen HZ, Reeser JW, Wing MR, Martin DM, Smith AM, Dao T, Samorodnitsky E, Paruchuri A, Miya J, Baker KR, Yu L, Timmers C, Dittmar K, Freud AG, Allenby P, Roychowdhury S
Title Tumor heterogeneity and acquired drug resistance in FGFR2-fusion-positive cholangiocarcinoma through rapid research autopsy.
Journal Cold Spring Harbor molecular case studies
Vol 5
Issue 4
Date 2019 08
URL
Abstract Text Cholangiocarcinoma is a highly aggressive and lethal malignancy, with limited treatment options available. Recently, FGFR inhibitors have been developed and utilized in FGFR-mutant cholangiocarcinoma; however, resistance often develops and the genomic determinants of resistance are not fully characterized. We completed whole-exome sequencing (WES) of 11 unique tumor samples obtained from a rapid research autopsy on a patient with FGFR-fusion-positive cholangiocarcinoma who initially responded to the pan-FGFR inhibitor, INCB054828. In vitro studies were carried out to characterize the novel FGFR alteration and secondary FGFR2 mutation identified. Multisite WES and analysis of tumor heterogeneity through subclonal inference identified four genetically distinct cancer cell populations, two of which were only observed after treatment. Additionally, WES revealed an FGFR2 N549H mutation hypothesized to confer resistance to the FGFR inhibitor INCB054828 in a single tumor sample. This hypothesis was corroborated with in vitro cell-based studies in which cells expressing FGFR2-CLIP1 fusion were sensitive to INCB054828 (IC50 value of 10.16 nM), whereas cells with the addition of the N549H mutation were resistant to INCB054828 (IC50 value of 1527.57 nM). Furthermore, the FGFR2 N549H secondary mutation displayed cross-resistance to other selective FGFR inhibitors, but remained sensitive to the nonselective inhibitor, ponatinib. Rapid research autopsy has the potential to provide unprecedented insights into the clonal evolution of cancer throughout the course of the disease. In this study, we demonstrate the emergence of a drug resistance mutation and characterize the evolution of tumor subclones within a cholangiocarcinoma disease course.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
FGFR2 CLIP1 FGFR2 - CLIP1 fusion gain of function - predicted FGFR2-CLIP1 results from the fusion of FGFR2 and CLIP1, and results in increased PI3K, MAPK, and FGFR2 signaling in culture (PMID: 31371345), and therefore, is predicted to lead to a gain of protein function. FGFR2-CLIP1 has been identified in metastatic cholangiocarcinoma (PMID: 31371345).
FGFR2 N549H missense gain of function FGFR2 N549H lies within the protein kinase domain of the Fgfr2 protein (UniProt.org). N549H demonstrates resistance to FGFR inhibitors in the context of FGFR2-CLIP1 in culture (PMID: 31371345), and confers a gain of function to the Fgfr2 protein as indicated by disengagement of autoinhibitory mechanisms thereby resulting in constitutive activation and downstream pathway activation (PMID: 17525745, PMID: 17803937), and results in elevated kinase activity compared to wild-type Fgfr2 protein in substrate phosphorylation assays (PMID: 28166054). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Dovitinib (TKI258) treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 cholangiocarcinoma predicted - sensitive Pemigatinib Case Reports/Case Series Actionable In a clinical case study, a cholangiocarinoma patient harboring FGFR2-CLIP1 demonstrated a partial response following treatment with Pemazyre (pemigatinib) (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor sensitive Infigratinib Preclinical - Cell culture Actionable In a preclinical study, Infigratinib (BGJ398) treatment inhibited viability of a transformed cell line expressing FGFR2-CLIP1 in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor resistant Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Balversa (erdafitinib) treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor resistant Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Pemazyre (pemigatinib) treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor resistant AZD4547 Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to AZD4547 treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor sensitive Pemigatinib Preclinical - Cell culture Actionable In a preclinical study, Pemazyre (pemigatinib) treatment inhibited viability of a transformed cell line expressing FGFR2-CLIP1 in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) treatment inhibited viability of a transformed cell line expressing FGFR2-CLIP1 in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor sensitive Ponatinib Preclinical - Cell culture Actionable In a preclinical study, Iclusig (ponatinib) treatment inhibited viability of a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H cholangiocarcinoma predicted - resistant Pemigatinib Case Reports/Case Series Actionable In a clinical case study, a cholangiocarinoma patient harboring FGFR2-CLIP1 demonstrated an initial partial response following treatment with Pemazyre (pemigatinib), but progressed after 5 months, and was determined to have an acquired FGFR2 N549H mutation (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor resistant Dovitinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing FGFR2-CLIP1 demonstrated resistance to Dovitinib (TKI258) treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 FGFR2 N549H Advanced Solid Tumor resistant Infigratinib Preclinical - Cell culture Actionable In a preclinical study, a transformed cell line expressing both FGFR2-CLIP1 and FGFR2 N549H demonstrated resistance to Infigratinib (BGJ398) treatment in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor sensitive AZD4547 Preclinical - Cell culture Actionable In a preclinical study, AZD4547 treatment inhibited viability of a transformed cell line expressing FGFR2-CLIP1 in culture (PMID: 31371345). 31371345
FGFR2 - CLIP1 Advanced Solid Tumor sensitive Erdafitinib Preclinical - Cell culture Actionable In a preclinical study, Balversa (erdafitinib) treatment inhibited viability of a transformed cell line expressing FGFR2-CLIP1 in culture (PMID: 31371345). 31371345